Type 2 diabetes (T2D) has become a major public health issue in both India and the United States (US). In consideration of its epidemiological burden and the related population health disparities, there have been continued efforts to understand the factors underlying its phenotypic expression. Given its significance as a binational healthcare problem, the National Institutes of Health (NIH RFA-DK-14-006) and the Indian Council: of Medical Research (ICMR) have come together to announce funding opportunities to support Binational Collaborative Research Partnerships (CRPs) on diabetes research. There is a paucity of genetic epidemiologic investigations of T2D in India. In response to this initiative, we have formed a new CRP involving two US institutions and three Indian institutions to evaluate genetic determinants of T2D among four endogamous ethnic groups (EEGs) using pedigree-based data sets from two North and two South Indian states. The specific aims of this joint experimental/developmental proposal are detailed below, which will be accomplished by Indian or US partners or both of them jointly. As part of Aim 1a, we will recruit 1500 individuals from ~60 large families from three genetically and culturally diverse EEGs from the states of Rajasthan (Agarwal EEG), Tamil Nadu (Chettiar EEG), and Andhra Pradesh (Reddy EEG); 500 individuals from 20 large families (25 members per family) from each EEG will be ascertained on T2D probands. The family- phenotypic- and genotypic data, from a Sikh Khatri EEG from the state of Punjab are already collected and will be available for this study. Clinical data related to T2D and information on environmental covariates (e.g., diet and physical activity) will be collected (Aim 1b). Through Aims 2a and 2b, several genetic analyses will be conducted such as determination of heritability of T2D, and comparative analyses will be performed between Indian populations and the US multi-ethnic populations including European Americans, African Americans, and Mexican Americans as they relate to T2D pathogenesis and pathophysiology. Most importantly, we will pursue genetic regions harboring 8 T2D susceptibility loci previously identified in South Asians including the Punjabi Sikh population by performing targeted resequencing, using samples (N=336) from the Punjabi Sikh EEG families and assess associations between T2D and rare and low frequency variants detected through sequencing (Aim 3a). The best associated ~200 genetic variants with T2D will be confirmed in an additional sample of 4,000 Sikh individuals (Aim 3b). As part of Aim 4, the best associated ~100 SNPs from Aim 3b together with ~100 genetic variants representing the established T2D susceptibility loci from non-Indian populations will be confirmed in the three EEGs enrolled as part of Aim 1. Maximizing the expertise, research experience, and resources of the US and Indian collaborative teams, our study will lay a strong foundation to critically examine genetic, social and cultural differences among the Indian EEGs. To our knowledge, this is the first Indo-US collaborative effort to apply pedigree-based design and sequencing technologies to identify novel causal genes and molecular pathways associated with T2D.